Cardiovascular pathologies remain the most prevalent cause of morbidity and death in the USA. Cell based therapy which involves mobilization and engraftment of stem cells offers a potential alternative for treatment of myocardial infarction patients. Despite encouraging results from experimental animal studies and human clinical trials, heart cell therapy is afflicted with multiple caveats including rapid and massive death of the donor cells after engraftment in the recipient heart. Our novel approach of combining pharmacological treatment approach with stem cell engraftment results in significantly higher survival of the donor cells. Amongst the various pharmacological strategies for potentiating stem cells repair, clinically relevant agents are more appealing. Phosphodiesterase (PDE) has wide distribution in the biological system including stem cells and provides a potential target for pharmacological treatment of the cells due to its pivotal role in critical signaling pathways relevant to cell survival and differentiation. Moreover, this innovative approach will be safe due to the use of clinically approved pharmacological agents for PDE inhibition. We posit that use of Tadalafil, a long acting PDE-5A inhibitor would be cardioprotective and can enhance stem cell survival and promote their angiomyogenic differentiation after transplantation into the infarcted heart. To address this, we propose the following four hypotheses. Hypothesis 1: Suppression of PDE5A using a long acting inhibitor, Tadalafil, will promote MSCs survival, engraftment and angiomyogenic differentiation in the infarcted myocardium. Hypothesis 2 has been designed to study that inhibition of PDE5A promotes stem cell proliferation, engraftment and differentiation via NO-PKG signaling pathway. Hypothesis 3 will determine that PDE5A inhibition in the heart simultaneously reduces myocardial ischemic injury and accelerates stem cell survival and differentiation of the engrafted MSCs in the infarcted myocardium. Hypothesis 4 will test whether extended inhibition of PDE5A in MSCs induces paracrine mediators for cardiac protection and regeneration. The validity of these hypotheses will be assessed in vitro as well as in vivo experimental animal models and will involve multidisciplinary approach based on molecular biology and proteomic studies, immunocytochemistry, electrophysiology, flow cytometry, confocal imaging, and electron microscopy. The data thus generated at cellular and molecular levels will be integrated with the results from experimental animal models to elucidate the mechanistic basis of functional outcome at organ level. Thus the proposed studies using the safe and clinically approved PDE5A inhibitors may identify a potential therapeutic role for these compounds for stem cell based de novo myocardial regeneration.